Ying Qing Chen

All Publications

• Estimating attributable risk functions for censored time-to-event in disease prevention research. Lifetime data analysis Chen, Y. Q., Wang, Y., Zhang, X., Prentice, R. L. 2026; 32 (2)

  Abstract

  In disease prevention research, researchers often need to assess a prevention strategy that targets key disease-associated risk factors to reduce a population's disease burden. In this article, the fraction of the total disease burden associated with the risk factors targeted by the prevention strategy is calculated by time-varying attributable risk functions (ARF) when the disease outcome is censored time-to-event. We study some generic ARFs and develop nonparametric and semiparametric model-based procedures to estimate, compare, and predict ARFs. In addition to numerical simulation studies, we demonstrate the use of ARFs for a human immunodeficiency virus (HIV) behavior intervention trial in prevention of HIV transmissions among men who have sex with men (MSM).

  View details for DOI 10.1007/s10985-026-09704-2

  View details for PubMedID 41888481

• What drives adolescent girls and young women's decisions to persist on PrEP? Results of a comparative qualitative study from a DREAMS program in western Kenya. AIDS care Matsuno, A., Tollefson, D., Cover, J., Obong'o, C., Gamba, H., Chen, Y. Q., Duerr, A. 2025: 1-11

  Abstract

  Oral pre-exposure prophylaxis (PrEP) is a valuable tool to help end HIV, but persistent PrEP use is low amongst adolescent girls and young women (AGYW) in sub-Saharan Africa (SSA), who are at high risk for HIV. To improve persistent PrEP use in AGYW, more research is needed to understand what drives their decisions to continue with PrEP. We conducted a thematic, comparative qualitative analysis of in-depth interviews with 32 AGYW who participated in PEPFAR's DREAMS program in western Kenya: 16 were randomly sampled among those who persisted with PrEP and 16 among those who discontinued. We compared results between these groups to explore drivers for the decision to persist with PrEP. We interpreted findings using the Integrated Behavior Model, which posits that the decision to persist is influenced by attitudes, social norms and personal agency. Three themes emerged that illuminated AGYW's decision to persist with PrEP. First, having positive attitudes towards PrEP was insufficient to ensure persistence in absence of correct knowledge. All AGYW were positive about PrEP, but those who discontinued often had insufficient/misinformation about PrEP, specifically on its appropriate use during pregnancy/breastfeeding. Second, support from family and friends was critical to overcome societal stigma and could counter lack of support from romantic partners. Third, strong mentors supported PrEP persistence by increasing self-agency, but this was secondary in importance to the need for robust knowledge and social support. To improve PrEP persistence amongst AGYW in SSA, PrEP programs may benefit from increasing education delivered to AGYWs and their communities, specifically family and friends. In particular, messages that PrEP may be used when pregnant/breastfeeding should be reinforced. Other health programs for AGYWs may also benefit from an increased focus on educational messaging to program recipients and people in their existing social networks.

  View details for DOI 10.1080/09540121.2025.2570098

  View details for PubMedID 41082548

• Use of Coronary Artery Bypass Graft Surgery and Percutaneous Coronary Intervention and Associated Outcomes in the ISCHEMIA Trial. American heart journal White, H. D., O'Brien, S. M., Boden, W. E., Fremes, S. E., Bangalore, S., Reynolds, H. R., Stone, G. W., Ali, Z. A., Parakh, N., Lopez-Sendon, J. L., Wang, Y., Chen, Y. Q., Mark, D. B., Chaitman, B. R., Spertus, J. A., Maron, D. J., Hochman, J. S., ISCHEMIA Research Group 2025

  Abstract

  BACKGROUND: In the ISCHEMIA Trial, 5179 patients with stable coronary disease were randomized to initial invasive or conservative management.METHODS: PCI was recommended with a SYNTAX score 0-22 (low) and CABG with a SYNTAX score ≥33 (high). Either could be recommended for intermediate scores. The composite primary outcome was cardiovascular death, MI, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. There were two cohorts in this analysis. The descriptive cohort included patients who underwent CABG or PCI within 180 days of randomization and had no primary outcome before revascularization. The comparative cohort excluded participants with prior CABG, single vessel disease, SYNTAX score ≥ 45, and without core laboratory assessment. We focused on the intermediate (23-32) SYNTAX comparative group for which either CABG or PCI could be recommended.RESULTS: For 1935 patients in the descriptive cohort (485 CABG, 1450 PCI), the SYNTAX score was 27.3 ± 11.0 in the CABG group and 15.3 ± 8.6 in the PCI group, p<0.0001. Most patients with low SYNTAX scores underwent PCI (87.1%), while most with high SYNTAX scores underwent CABG (72.6%). For the 1203 patients (385 CABG, 818 PCI) in the entire comparative cohort, the adjusted 4-year primary event rate was 14.5% for CABG and 13.2% for PCI (difference 1.3%, 95% CI, -4.9% to 7.7%). For the 346 patients (163 CABG, 183 PCI) in the intermediate SYNTAX group, the adjusted 4-year primary event rate was 10.6% for CABG and 18.3% for PCI (difference -7.6%, 95% CI, -16.1% to 0.9%).CONCLUSIONS: Selection of revascularization method resulted in more PCI in the low SYNTAX group and more CABG in the high SYNTAX group. There was no statistical evidence of a difference between PCI and CABG in the intermediate SYNTAX group but the CIs are broad, reflecting uncertainty.CLINICAL TRIALS:GOV IDENTIFIER: NCT01471522; https://clinicaltrials.gov/ct2/show/NCT01471522.

  View details for DOI 10.1016/j.ahj.2025.05.009

  View details for PubMedID 40404111

• Absorbing Markov chain model of PrEP drug adherence to estimate adherence decay rate and probability distribution in clinical trials JOURNAL OF THEORETICAL BIOLOGY Dale, R., He, H., Chen, Y. 2025; 604: 112086

  Abstract

  Pre-exposure prophylaxis (PrEP) is increasingly used to prevent the transmission of H.I.V. in at-risk populations. However, PrEP users may discontinue use of the medicine due to side effects, lower perceived risk, or other reasons. The usage metrics of 594 individuals was tracked over 350 days using the Wisepill electronic monitoring system. We model the PrEP drug adherence level using an absorbing Markov chain with a unique absorbing state. The transition matrix T obtained from the Wisepill data will have a trivial eigenvector (eigendistribution) associated with the first (i.e., largest) eigenvalue 1. The 2nd eigenvalue(s) then become important in determining the asymptotic behavior of the Markov chain, dictating how fast the Markov chain decays to the absorbing state. Under a fairly general assumption, we prove that the second positive eigenvalue is unique and the corresponding eigenvector will have nonnegative entries with exceptions at absorbing states. In addition, we define the asymptotic half life of the absorbing Markov chain directly from the 2nd eigenvalue. We then determine the 2nd eigenvalue of T and the asymptotic half life of the Markov chain, which turns out to be very close to the real half life of the Markov chain. Finally, we interpret the 2nd eigenvector as the relative probability distribution of X∞ with respect to the decay rate of the 2nd eigenvalue. By applying these methods to the Wisepill data, we estimate the half-life of population adherence to be 46 weeks. The bi-weekly decay rate observed in these data from 90 to 100 % adherence is 3 %. This work produces an estimate at which adherence falls over time, given no external intervention is applied. These results suggest an eigenvector-based approach to estimate adherence trends, as well as the timing of interventions to improve adherence.

  View details for DOI 10.1016/j.jtbi.2025.112086

  View details for Web of Science ID 001448079100001

  View details for PubMedID 40086122

  View details for PubMedCentralID PMC12037977

• On Data-Enriched Logistic Regression MATHEMATICS Zheng, C., Dasgupta, S., Xie, Y., Haris, A., Chen, Y. 2025; 13 (3)

  View details for DOI 10.3390/math13030441

  View details for Web of Science ID 001418671500001

• Semiparametric Trend Analysis for Stratified Recurrent Gap Times Under Weak Comparability Constraint. Statistics in biosciences Liu, P., Huang, Y., Chan, K. C., Chen, Y. Q. 2023; 15 (2): 455-474

  Abstract

  Recurrent event data are frequently encountered in many longitudinal studies where each individual may experience more than one event. Wang and Chen (Biometrics 56(3):789-794, 2000) proposed a comparability constraint to estimate the time trend for the gap times, where the gap time pairs that satisfy the constraint have the same conditional distribution. However, the comparable paired gap times are also independent. Therefore, the comparable gap time pairs will be subject to a stronger constraint than needed for the estimation. Thus their procedure is subject to information loss. Under the accelerated failure time model, we propose a new comparability constraint that can overcome the drawback mentioned above. The gap time pairs being selected by the proposed comparability constraint will still have the same distribution, but they do not need to be independent of each other. We showed that the proposed comparability constraint will utilize more gap time data pairs than the strong comparability. And we showed via various simulation studies that the variance will be smaller than Wang and Chen's (2000) estimator. We apply the proposed method to the HIV Prevention Trial Network 052 study.

  View details for DOI 10.1007/s12561-023-09376-8

  View details for PubMedID 39512240

  View details for PubMedCentralID PMC11542620

• Semiparametric Trend Analysis for Stratified Recurrent Gap Times Under Weak Comparability Constraint STATISTICS IN BIOSCIENCES Liu, P., Huang, Y., Chan, K., Chen, Y. 2023

  View details for DOI 10.1007/s12561-023-09376-8

  View details for Web of Science ID 000999954100002

• Population-Level Effectiveness of an Inactivated Whole-Virion COVID-19 Vaccine: A Test Negative Case-Control Study in the Dominican Republic. Open forum infectious diseases Pérez-Then, E., Miric, M., Qian, H. Z., Chen, Y. Q., Wang, Y., Vallejo, V., Quezada, W., Flaquer, M., Olivo, J., Castillo, J., García, N., Calderón, K., Cueto, S., Veras, B., Russo, M., Jiménez, I., Guzmán, S., Garabito, L., Cueto, E., Colombo, F., Taveras, D., Torres, D., Baez, J., Yunen, J., Koenig, E., Pérez, E., López, O., Severino Medina, F. E., Wang, X., Shao, Y., Vermund, S. H. 2023; 10 (3): ofad075

  Abstract

  A continuing nationwide vaccination campaign began in the Dominican Republic on February 16, 2021 to prevent severe consequences of acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Estimates of vaccine effectiveness under real-world conditions are needed to support policy decision making and inform further vaccine selection.We conducted a test-negative case-control study to assess the real-world effectiveness of nationwide coronavirus disease 2019 (COVID-19) vaccination program using an inactivated vaccine (CoronaVac) on preventing symptomatic SARS-CoV-2 infections and hospitalizations from August to November 2021 in the Dominican Republic. Participants were recruited from 10 hospitals in 5 provinces to estimate the effectiveness of full immunization (≥14 days after receipt of the second dose) and partial immunization (otherwise with at least 1 dose ≥14 days after receipt of the first dose).Of 1078 adult participants seeking medical care for COVID-19-related symptoms, 395 (36.6%) had positive polymerase chain reaction (PCR) tests for SARS-CoV-2; 142 (13.2%) were hospitalized during 15 days of follow up, including 91 (23%) among 395 PCR-positive and 51 (7.5%) among 683 PCR-negative participants. Full vaccination was associated with 31% lower odds of symptomatic infection (odds ratio [OR], 0.69; 95% confidence interval [CI], 0.52-0.93) and partial vaccination was associated with 49% lower odds (OR, 0.51; CI, 0.30-0.86). Among 395 PCR-positive participants, full vaccination reduced the odds of COVID-19-related hospitalization by 85% (OR, 0.15; 95% CI, 0.08-0.25) and partial vaccination reduced it by 75% (OR, 0.25; 95% CI, 0.08-0.80); full vaccination was associated with reduced use of assisted ventilation by 73% (OR, 0.27; 95% CI, 0.15-0.49).Given the ancestral and delta viral variants circulating during this study period, our results suggest that the inactivated COVID-19 vaccine offered moderate protection against symptomatic SARS-CoV-2 infections and high protection against COVID-19-related hospitalizations and assisted ventilation. This is reassuring given that, as of August 2022, an estimated 2.6 billion inactivated CoronaVac vaccine doses had been administered worldwide. This vaccine will become a basis for developing multivalent vaccine against the currently circulating omicron variant.

  View details for DOI 10.1093/ofid/ofad075

  View details for PubMedID 36998630

  View details for PubMedCentralID PMC10043129

• On a simple estimation of the proportional odds model under right truncation. Lifetime data analysis Liu, P., Chan, K. C., Chen, Y. Q. 2023

  Abstract

  Retrospective sampling can be useful in epidemiological research for its convenience to explore an etiological association. One particular retrospective sampling is that disease outcomes of the time-to-event type are collected subject to right truncation, along with other covariates of interest. For regression analysis of the right-truncated time-to-event data, the so-called proportional reverse-time hazards model has been proposed, but the interpretation of its regression parameters tends to be cumbersome, which has greatly hampered its application in practice. In this paper, we instead consider the proportional odds model, an appealing alternative to the popular proportional hazards model. Under the proportional odds model, there is an embedded relationship between the reverse-time hazard function and the usual hazard function. Building on this relationship, we provide a simple procedure to estimate the regression parameters in the proportional odds model for the right truncated data. Weighted estimations are also studied.

  View details for DOI 10.1007/s10985-022-09584-2

  View details for PubMedID 36602639

• Pregnancy rates and clinical outcomes among women living with HIV enrolled in HPTN 052 AIDS CARE-PSYCHOLOGICAL AND SOCIO-MEDICAL ASPECTS OF AIDS/HIV Zangeneh, S. Z., Wilson, E. A., Ahluwalia, S., Donnell, D. J., Chen, Y. Q., Grinsztejn, B., Melo, M. G., Godbole, S. V., Hosseinipour, M. C., Taha, T., Kumwenda, J., McCauley, M., Cohen, M. S., Nielsen-Saines, K. 2022: 1-9

  Abstract

  HPTN 052 was a multi-country clinical trial of cART for preventing heterosexual HIV-1 transmission. The study allowed participation of pregnant women and provided access to cART and contraceptives. We explored associations between pregnancy and clinical measures of HIV disease stage and progression. Of 869 women followed for 5.70 (SD = 1.62) years, 94.7% were married/cohabitating, 96% initiated cART, and 76.3% had >2 past pregnancies. Of 337 women who experienced pregnancy, 89.3% were from countries with lower contraceptive coverage, 56.1% first started cART with PI-based regimens and 57.6% were 25-34 years old. Mean cART duration and condom use were similar among pregnant and nonpregnant individuals. Adjusting for confounders, viral load suppression (VLS) was not (aHR(CI) = 0.82(0.61, 1.08)) and CD4 was slightly associated with decreased rates of first pregnancy over time (aHR(CI) = 0.9(0.84, 0.95)); baseline VLS was associated with increased (aRR(CI) = 2.48(1.71, 3.59)) and baseline CD4 was slightly associated with decreased number of pregnancies (aRR(CI) = 0.9(0.85,0.96)) over study duration. Partner seroconversion was univariably associated with higher rates of first pregnancy (HR(CI) = 2.02(1.32,3.07)). Despite a background of higher maternal morbidity and mortality rates, our findings suggest that becoming pregnant does not pose a threat to maternal health in women with HIV when there is access to medical care and antiretroviral treatment.

  View details for DOI 10.1080/09540121.2022.2141187

  View details for Web of Science ID 000899520400001

  View details for PubMedID 36524872

• Sexual behavior and medication adherence in men who have sex with men participating in a pre-exposure prophylaxis study of combinations of Maraviroc, Tenofovir Disoproxil Fumarate and/or Emtricitabine (HPTN 069/ACTG 5305) AIDS AND BEHAVIOR Mayer, K. H., Yuhas, K., Amico, K., Wilkin, T., Landovitz, R. J., Richardson, P., Marzinke, M. A., Eshleman, S. H., Cottle, L. M., Marcus, C., Chege, W., Rinehart, A. R., Rooney, J. F., Andrew, P., Salata, R. A., Magnus, M., Farley, J. E., Liu, A. Y., Frank, I., Ho, K., Santana, J., Stekler, J. D., Chen, Y. Q., McCauley, M., Gulick, R. M. 2022

  Abstract

  HPTN 069/ACTG 5305 was designed to evaluate potential new PrEP regimens that included maraviroc, tenofovir disoproxil fumarate, and/or emtricitabine. The current analyses assessed antiretroviral (ARV) plasma concentrations in relation to sexual behavior in 224 cisgender men who have sex with men and 2 transgender women at risk for HIV. Poisson generalized estimating equations (GEE) regression were used to test for associations between self-reported sexual behavior, sociodemographic, behavioral variables, and study drug levels The median (IQR) age was 30 [25, 37] years old; 48.2% had completed college; 27.4% were Black and 21.7% Latino. At weeks 24 and 48, one third of participants reported condomless anal sex (CAS) in the prior month with more than one partner. CAS was associated with daily ARV drug use (χ2 = 12.64, p = 0.002). Older individuals and those with greater education were more likely to ingest ARV drugs daily (χ2 = 9.36, p = 0.009 and χ2 = 8.63, p = 0.013, respectively), while neither race nor ethnicity was associated with daily ARV drug use. Participants who reported recent condomless anal sex and/or advanced education had higher rates of daily ARV drug use. These data support the need for ongoing adherence counseling in clinical trials of new PrEP modalities.

  View details for DOI 10.1007/s10461-022-03736-z

  View details for Web of Science ID 000809325200006

  View details for PubMedID 35687192

• A Surrogate Measure for Time-Varying Biomarkers in Randomized Clinical Trials. Mathematics (Basel, Switzerland) Zhuang, R., Xia, F., Wang, Y., Chen, Y. Q. 2022; 10 (4)

  Abstract

  Clinical trials with rare or distant outcomes are usually designed to be large in size and long term. The resource-demand and time-consuming characteristics limit the feasibility and efficiency of the studies. There are motivations to replace rare or distal clinical endpoints by reliable surrogate markers, which could be earlier and easier to collect. However, statistical challenges still exist to evaluate and rank potential surrogate markers. In this paper, we define a generalized proportion of treatment effect for survival settings. The measure's definition and estimation do not rely on any model assumption. It is equipped with a consistent and asymptotically normal non-parametric estimator. Under proper conditions, the measure reflects the proportion of average treatment effect mediated by the surrogate marker among the group that would survive to mark the measurement time under both intervention and control arms.

  View details for DOI 10.3390/math10040584

  View details for PubMedID 39512426

  View details for PubMedCentralID PMC11542621

• A surrogate measure for time-varying biomarkers in randomized clinical trials Mathematics Y, Z., F, X., Y, W., Y. Q., C. 2022; 10 (4): 584

  View details for DOI 10.3390/math10040584

• Uptake of antiretroviral treatment and viral suppression among men who have sex with men and transgender women in sub-Saharan Africa in an observational cohort study: HPTN 075 INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES Palumbo, P. J., Zhang, Y., Clarke, W., Breaud, A., Sivay, M., Cummings, V., Hamilton, E. L., Guo, X., Ogendo, A., Kayange, N., Panchia, R., Dominguez, K., Chen, Y. Q., Sandfort, T. G. M., Eshleman, S. H. 2021; 104: 465–70

  Abstract

  HPTN 075 enrolled men who have sex with men (MSM) and transgender women (TGW) in sub-Saharan Africa. Persons in HIV care or on antiretroviral treatment (ART) were not eligible to enroll. We evaluated antiretroviral (ARV) drug use, viral suppression, and drug resistance in this cohort over a 12-month follow-up period.Assessments included 64 participants with HIV (39 MSM, 24 TGW, and one gender not specified). ARV drugs were detected using a qualitative assay. Viral load (VL) and drug resistance testing were performed using commercial assays.Over 12 months, the proportion of participants using ARV drugs increased from 28.1% to 59.4% and the proportion with VLs <400 copies/mL increased from 21.9% to 57.8%. The rate of ART failure (detection of drugs without viral suppression) was similar at screening and 12 months (12.0% and 11.1%, respectively) and was similar among MSM and TGW. Two participants developed HIV drug resistance during follow-up.Over 12 months, ARV drug use in the cohort more than doubled and viral suppression increased nearly threefold without a significant increase in ART failure or drug resistance. These results suggest that ART can be successfully scaled up for HIV prevention and treatment in this high-risk population.

  View details for DOI 10.1016/j.ijid.2020.12.085

  View details for Web of Science ID 000632937400024

  View details for PubMedID 33440260

  View details for PubMedCentralID PMC8091139

• HIV incidence in a multinational cohort of men and transgender women who have sex with men in sub-Saharan Africa: Findings from HPTN 075 PLOS ONE Sandfort, T. G. M., Mbilizi, Y., Sanders, E. J., Guo, X., Cummings, V., Hamilton, E. L., Akelo, V., Panchia, R., Dominguez, K., Stirratt, M. J., Chege, W., Lucas, J., Gaydos, C. A., Chen, Y. Q., Eshleman, S. H. 2021; 16 (2): e0247195

  Abstract

  Few studies have assessed HIV incidence in men who have sex with men (MSM) and transgender women (TGW) in sub-Saharan Africa (SSA). We assessed HIV incidence and its correlates among MSM and TGW in SSA enrolled in the prospective, multi-country HIV Prevention Trials Network (HPTN) 075 study, conducted from 2015 to 2017. Participants were enrolled at four sites in SSA (Kisumu, Kenya; Blantyre, Malawi; Cape Town and Soweto, South Africa). Eligible participants reported male sex assignment at birth, were 18 to 44 years of age, and had engaged in anal intercourse with a man in the preceding three months. Participation involved five study visits over 12 months. Visits included behavioral assessments and testing for HIV and sexually transmitted infections. Twenty-one of 329 persons acquired HIV during the study [incidence rate: 6.96/100 person-years (PY) (95% CI: 4.3, 10.6)]. Among TGW, HIV incidence was estimated to be 8.4/100 PY (95% CI: 2.3, 21.5). Four participants were found to have acute HIV infection at their first HIV-positive visit. HIV incidence varied among the four study sites, ranging from 1.3/100 PY to 14.4/100 PY. In multivariate longitudinal analysis, factors significantly associated with HIV acquisition were engagement in unprotected receptive anal intercourse [adjusted hazard ratio (AHR) 5.8, 95% confidence interval (CI): 2.4, 14.4] and incident rectal gonorrhea and/or chlamydia (AHR: 2.7, 95% CI: 1.1, 6.8). The higher HIV incidence in Cape Town compared to Blantyre could be explained by the higher prevalence of several risk factors for HIV infection among participants in Cape Town. Annual HIV incidence observed in this study is substantially higher than reported HIV incidence in the general populations in the respective countries and among MSM in the United States. Intensification of HIV prevention efforts for MSM and TGW in SSA is urgently needed.

  View details for DOI 10.1371/journal.pone.0247195

  View details for Web of Science ID 000624536800030

  View details for PubMedID 33630925

  View details for PubMedCentralID PMC7906338

• Evaluation of Phylogenetic Methods for Inferring the Direction of Human Immunodeficiency Virus (HIV) Transmission: HIV Prevention Trials Network (HPTN) 052. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Zhang, Y., Wymant, C., Laeyendecker, O., Grabowski, M. K., Hall, M., Hudelson, S., Piwowar-Manning, E., McCauley, M., Gamble, T., Hosseinipour, M. C., Kumarasamy, N., Hakim, J. G., Kumwenda, J., Mills, L. A., Santos, B. R., Grinsztejn, B., Pilotto, J. H., Chariyalertsak, S., Makhema, J., Chen, Y. Q., Cohen, M. S., Fraser, C., Eshleman, S. H. 2021; 72 (1): 30-37

  Abstract

  Phylogenetic analysis can be used to assess human immunodeficiency virus (HIV) transmission in populations. We inferred the direction of HIV transmission using whole-genome HIV sequences from couples with known linked infection and known transmission direction.Complete next-generation sequencing (NGS) data were obtained for 105 unique index-partner sample pairs from 32 couples enrolled in the HIV Prevention Trials Network (HPTN) 052 study (up to 2 samples/person). Index samples were obtained up to 5.5 years before partner infection; partner samples were obtained near the time of seroconversion. The bioinformatics method, phyloscanner, was used to infer transmission direction. Analyses were performed using samples from individual sample pairs, samples from all couples (1 sample/person; group analysis), and all available samples (multisample group analysis). Analysis was also performed using NGS data from defined regions of the HIV genome (gag, pol, env).Using whole-genome NGS data, transmission direction was inferred correctly (index to partner) for 98 of 105 (93.3%) of the individual sample pairs, 99 of 105 (94.3%) sample pairs using group analysis, and 31 of the 32 couples (96.9%) using multisample group analysis. There were no cases where the incorrect transmission direction (partner to index) was inferred. The accuracy of the method was higher with greater time between index and partner sample collection. Pol region sequences performed better than env or gag sequences for inferring transmission direction.We demonstrate the potential of a phylogenetic method to infer the direction of HIV transmission between 2 individuals using whole-genome and pol NGS data.

  View details for DOI 10.1093/cid/ciz1247

  View details for PubMedID 31922537

  View details for PubMedCentralID PMC7823077

• Measuring Surrogacy in Clinical Research With an Application to Studying Surrogate Markers for HIV Treatment-as-Prevention STATISTICS IN BIOSCIENCES Zhuang, R., Chen, Y. 2020; 12 (3): 295–323

  Abstract

  In clinical research, validated surrogate markers are highly desirable in study design, monitoring, and analysis, as they do not only reduce the required sample size and follow-up duration, but also facilitate scientific discoveries. However, challenges exist to identify a reliable marker. One particular statistical challenge arises on how to measure and rank the surrogacy of potential markers quantitatively. We review the main statistical methods for evaluating surrogate markers. In addition, we suggest a new measure, the so-called "population surrogacy fraction of treatment effect," or simply the p-measure, in the setting of clinical trials. The p-measure carries an appealing population impact interpretation and supplements the existing statistical measures of surrogacy by providing "absolute" information. We apply the new measure along with other prominent measures to the HIV Prevention Trial Network 052 Study, a landmark trial for HIV/AIDS treatment-as-prevention.

  View details for DOI 10.1007/s12561-019-09244-4

  View details for Web of Science ID 000585702200004

  View details for PubMedID 33737982

  View details for PubMedCentralID PMC7962622

• Introduction to Special Issue on 'Statistical Methods for HIV/AIDS Research' STATISTICS IN BIOSCIENCES Chen, Y. 2020; 12 (3): 263–66

  View details for DOI 10.1007/s12561-020-09296-x

  View details for Web of Science ID 000579725100001

  View details for PubMedID 33101525

  View details for PubMedCentralID PMC7569197

• The feasibility of recruiting and retaining men who have sex with men and transgender women in a multinational prospective HIV prevention research cohort study in sub-Saharan Africa (HPTN 075) JOURNAL OF THE INTERNATIONAL AIDS SOCIETY Sandfort, T. G. M., Hamilton, E., Marais, A., Guo, X., Sugarman, J., Chen, Y. Q., Cummings, V., Dadabhai, S., Dominguez, K., Panchia, R., Schnabel, D., Zulu, F., Reynolds, D., Radebe, O., Mbeda, C., Kamba, D., Kanyemba, B., Ogendo, A., Stirratt, M., Chege, W., Lucas, J., Fawzy, M., McKinstry, L. A., Eshleman, S. H. 2020; 23: e25600

  Abstract

  Men who have sex with men (MSM) and transgender women (TGW) in sub-Saharan Africa (SSA) are profoundly affected by HIV with high HIV prevalence and incidence. This population also faces strong social stigma and legal barriers, potentially impeding participation in research. To date, few multi-country longitudinal HIV research studies with MSM/TGW have been conducted in SSA. Primary objective of the HIV Prevention Trials Network (HPTN) 075 study was to assess feasibility of recruiting and retaining a multinational prospective cohort of MSM/TGW in SSA for HIV prevention research.HPTN 075, conducted from 2015 to 2017, was designed to enroll 400 MSM/TGW at four sites in SSA (100 per site: Kisumu, Kenya; Blantyre, Malawi; Cape Town, South Africa; and Soweto, South Africa). The number of HIV-positive persons was capped at 20 per site; HIV-positive persons already in care were excluded from participation. The one-year study included five biobehavioural assessments. Community-based input and risk mitigation protocols were included in study design and conduct.Of 624 persons screened, 401 were enrolled. One in five participants was classified as transgender. Main reasons for ineligibility included: (a) being HIV positive after the cap was reached (29.6%); (b) not reporting anal intercourse with a man in the preceding three months (20.6%); and (c) being HIV positive and already in care (17.5%). Five (1.2%) participants died during the study (unrelated to study participation). 92.9% of the eligible participants (368/396) completed the final study visit and 86.1% participated in all visits. The main, overlapping reasons for early termination included being (a) unable to adhere to the visit schedule, predominantly because of relocation (46.4%), and (b) unable to contact the participant (32.1%). Participants reported strong motivation to participate and few participation barriers. Four participants reported social harms (loss of confidentiality and sexual harassment by study staff) that were successfully addressed.HPTN 075 successfully enrolled a multinational sample of MSM/TGW in SSA in a prospective HIV prevention research study with a high retention rate and few documented social harms. This supports the feasibility of conducting large-scale research trials in this population to address its urgent, unmet HIV prevention needs.

  View details for DOI 10.1002/jia2.25600

  View details for Web of Science ID 000576983100009

  View details for PubMedID 33000911

  View details for PubMedCentralID PMC7527761

• Persistence of oral pre-exposure prophylaxis (PrEP) among adolescent girls and young women initiating PrEP for HIV prevention in Kenya AIDS CARE-PSYCHOLOGICAL AND SOCIO-MEDICAL ASPECTS OF AIDS/HIV Tapsoba, J., Zangeneh, S. Z., Appelmans, E., Pasalar, S., Mori, K., Peng, L., Tao, J., Drain, P., Okomo, G., Bii, S., Mukabi, J., Zobrist, S., Brady, M., Obanda, R., Madiang, D., Cover, J., Duerr, A., Chen, Y., Obong'o, C. 2020: 1–9

  Abstract

  The Determined, Resilient, Empowered, AIDS-free, Mentored, and Safe (DREAMS) Initiative aims to reduce HIV infections among adolescent girls and young women (AGYW) in Africa. Oral pre-exposure prophylaxis (PrEP) is offered through DREAMS in Kenya to eligible AGYW in high burden counties including Kisumu and Homa Bay. This study examines PrEP persistence among AGYW in high burden community-based PrEP delivery settings. We evaluated PrEP persistence among AGYW in the DREAMS PrEP program in Kisumu and Homa Bay using survival analysis and programmatic PrEP refill data collected between March through December 2017. Among 1,259 AGYW who initiated PrEP during the study period, the median persistence time in the program was 56 days (95% CI: 49-58 days) and the proportion who persisted 3 months later was 37% (95% CI: 34-40%). Persistence varied by county (p < 0.001), age at PrEP initiation (p = 0.002), marital status (p = 0.008), transactional sex (p = 0.002), gender-based violence (GBV) experience (p = 0.009) and current school attendance (p = 0.001) at DREAMS enrollment. Persistence did not vary with orphan status, food insecurity, condom use, age at first sexual encounter or engagement in age-disparate sex at DREAMS enrollment. Targeted strategies are needed to improve AGYW retention in the PrEP program.

  View details for DOI 10.1080/09540121.2020.1822505

  View details for Web of Science ID 000571280600001

  View details for PubMedID 32951437

  View details for PubMedCentralID PMC7981281

• Trial designs for evaluating combination HIV prevention approaches HIV RESEARCH & CLINICAL PRACTICE Chen, Y., Peng, L., Wang, Y., Appelmans, E., Dasgupta, S., Fleming, T. R. 2020; 21 (2-3): 72–82

  Abstract

  Combination HIV prevention approaches that include both biomedical and non-biomedical interventions often hold greater promise to improve health outcomes and reduce the risk of HIV transmission.Evaluate the relative properties of four leading candidate trial designs - 'single-factor', 'multi-arm', 'all-in-one', and 'factorial' designs - for assessing individual and/or combination prevention intervention approaches.Monte-Carlo simulations are conducted, assuming a putative combination approach could choose its components from two candidate biomedical interventions, i.e. Treatment-as-Prevention (TasP) and Pre-exposure Prophylaxis (PrEP), and three candidate behavioral interventions, i.e. linkage-to-care, counseling, and use of condoms. Various scenarios for individual components' effect sizes, their possible interaction, and the sample size based on real clinical studies are considered.The all-in-one and factorial designs used to assess a combination approach and the multi-arm design used to assess multiple individual components are consistently more powerful than single-factor designs. The all-in-one design is powerful when the individual components are effective without negative interaction, while the factorial design is more consistently powerful across a broad array of settings.The multi-arm design is useful for evaluating single factor regimens, while the all-in-one and factorial designs are sensitive in assessing the overall efficacy when there is interest in combining individual component regimens anticipated to have complementary mechanisms. The factorial design is a preferred approach when assessing combination regimens due to its favorable power properties and since it is the only design providing direct insights about the contribution of individual components to the combination approach's overall efficacy and about potential interactions.

  View details for DOI 10.1080/25787489.2020.1798083

  View details for Web of Science ID 000555063900001

  View details for PubMedID 32698705

  View details for PubMedCentralID PMC7608072

• Variable Selection in Threshold Regression Model with Applications to HIV Drug Adherence Data STATISTICS IN BIOSCIENCES Saegusa, T., Ma, T., Li, G., Chen, Y., Lee, M. 2020; 12 (3): 376-398

  Abstract

  The threshold regression model is an effective alternative to the Cox proportional hazards regression model when the proportional hazards assumption is not met. This paper considers variable selection for threshold regression. This model has separate regression functions for the initial health status and the speed of degradation in health. This flexibility is an important advantage when considering relevant risk factors for a complex time-to-event model where one needs to decide which variables should be included in the regression function for the initial health status, in the function for the speed of degradation in health, or in both functions. In this paper, we extend the broken adaptive ridge (BAR) method, originally designed for variable selection for one regression function, to simultaneous variable selection for both regression functions needed in the threshold regression model. We establish variable selection consistency of the proposed method and asymptotic normality of the estimator of non-zero regression coefficients. Simulation results show that our method outperformed threshold regression without variable selection and variable selection based on the Akaike information criterion. We apply the proposed method to data from an HIV drug adherence study in which electronic monitoring of drug intake is used to identify risk factors for non- adherence.

  View details for DOI 10.1007/s12561-020-09284-1

  View details for Web of Science ID 000540966800001

  View details for PubMedID 33796162

  View details for PubMedCentralID PMC8009300

• Healthcare-related stigma among men who have sex with men and transgender women in sub-Saharan Africa participating in HIV Prevention Trials Network (HPTN) 075 study AIDS CARE-PSYCHOLOGICAL AND SOCIO-MEDICAL ASPECTS OF AIDS/HIV Mbeda, C., Ogendo, A., Lando, R., Schnabel, D., Gust, D. A., Guo, X., Akelo, V., Dominguez, K., Panchia, R., Mbilizi, Y., Chen, Y., Chege, W., Sandfort, T., HPTN 075 Protocol Team 2020; 32 (8): 1052–60

  Abstract

  ABSTRACT The inability to access health services when needed is a critical barrier to HIV prevention, treatment and care among men who have sex with men (MSM) and transgender women (TGW). Using data collected in HPTN 075, we explored factors associated with any experienced healthcare-related stigma. HPTN 075 was a cohort study to assess the feasibility of recruiting and retaining MSM and TGW in clinical trials in sub-Saharan Africa. Of 401 MSM and TGW enrolled at four sites (Kisumu, Kenya; Blantyre, Malawi; Cape Town, Soweto, South Africa) 397 contributed to the analysis (79.9% cis-gender and 20.1% TGW). Of these, (45.3%; 180/397) reported one or more of healthcare-related stigma experiences. Most frequently reported experiences included fear to seek healthcare services (36.3%) and avoiding seeking such services because of the discovery of MSM status (29.2%). Few men and TGW (2.5%) reported having been denied health services because of having sex with men. In multivariable analysis, more participants in Soweto [adjusted odds ratio (AOR) = 2.60] and fewer participants in Blantyre (AOR = 0.27) reported any healthcare-related stigma experiences, in comparison to participants in Kisumu. MSM and TGW that did not have a supportive gay community to rely on were more likely to report any healthcare-related stigma experiences (AOR = 1.46), whereas MSM and TGW who reported high social support and who never had engaged in transactional sex were less likely to report such experiences (AOR = 0.76 and AOR = 0.43, respectively). Our results suggest that encouraging support groups for MSM and TGW as well as training and sensitizing healthcare staff, and the general community, on MSM and TGW health issues and cultural competence may reduce stigma, improve access to healthcare, which could ultimately reduce HIV transmission.

  View details for DOI 10.1080/09540121.2020.1776824

  View details for Web of Science ID 000542822200001

  View details for PubMedID 32500722

  View details for PubMedCentralID PMC7368806

• On a Statistical Transmission Model in Analysis of the Early Phase of COVID-19 Outbreak STATISTICS IN BIOSCIENCES Zhu, Y., Chen, Y. 2021; 13 (1): 1–17

  Abstract

  Since December 2019, a disease caused by a novel strain of coronavirus (COVID-19) had infected many people and the cumulative confirmed cases have reached almost 180,000 as of 17, March 2020. The COVID-19 outbreak was believed to have emerged from a seafood market in Wuhan, a metropolis city of more than 11 million population in Hubei province, China. We introduced a statistical disease transmission model using case symptom onset data to estimate the transmissibility of the early-phase outbreak in China, and provided sensitivity analyses with various assumptions of disease natural history of the COVID-19. We fitted the transmission model to several publicly available sources of the outbreak data until 11, February 2020, and estimated lock down intervention efficacy of Wuhan city. The estimated R 0 was between 2.7 and 4.2 from plausible distribution assumptions of the incubation period and relative infectivity over the infectious period. 95% confidence interval of R 0 were also reported. Potential issues such as data quality concerns and comparison of different modelling approaches were discussed.

  View details for DOI 10.1007/s12561-020-09277-0

  View details for Web of Science ID 000523054500001

  View details for PubMedID 32292527

  View details for PubMedCentralID PMC7113380

• A regularized estimation approach for case-cohort periodic follow-up studies with an application to HIV vaccine trials BIOMETRICAL JOURNAL Zhao, H., Wu, Q., Gilbert, P. B., Chen, Y. Q., Sun, J. 2020; 62 (5): 1176–91

  Abstract

  This paper discusses regression analysis of the failure time data arising from case-cohort periodic follow-up studies, and one feature of such data, which makes their analysis much more difficult, is that they are usually interval-censored rather than right-censored. Although some methods have been developed for general failure time data, there does not seem to exist an established procedure for the situation considered here. To address the problem, we present a semiparametric regularized procedure and develop a simple algorithm for the implementation of the proposed method. In addition, unlike some existing procedures for similar situations, the proposed procedure is shown to have the oracle property, and an extensive simulation is conducted and it suggests that the presented approach seems to work well for practical situations. The method is applied to an HIV vaccine trial that motivated this study.

  View details for DOI 10.1002/bimj.201900180

  View details for Web of Science ID 000514617400001

  View details for PubMedID 32080888

  View details for PubMedCentralID PMC7768636

• Methods for generalized change-point models: with applications to human immunodeficiency virus surveillance and diabetes data STATISTICS IN MEDICINE Tapsoba, J., Wang, C., Zangeneh, S., Chen, Y. 2020; 39 (8): 1167–82

  Abstract

  In many epidemiological and biomedical studies, the association between a response variable and some covariates of interest may change at one or several thresholds of the covariates. Change-point models are suitable for investigating the relationship between the response and covariates in such situations. We present change-point models, with at least one unknown change-point occurring with respect to some covariates of a generalized linear model for independent or correlated data. We develop methods for the estimation of the model parameters and investigate their finite-sample performances in simulations. We apply the proposed methods to examine the trends in the reported estimates of the annual percentage of new human immunodeficiency virus (HIV) diagnoses linked to HIV-related medical care within 3 months after diagnosis using HIV surveillance data from the HIV prevention trial network 065 study. We also apply our methods to a dataset from the Pima Indian diabetes study to examine the effects of age and body mass index on the risk of being diagnosed with type 2 diabetes.

  View details for DOI 10.1002/sim.8469

  View details for Web of Science ID 000510844600001

  View details for PubMedID 31997385

  View details for PubMedCentralID PMC7260994

• Adjusted time-varying population attributable hazard in case-control studies STATISTICAL METHODS IN MEDICAL RESEARCH Zhao, W., Zheng, J., Chen, Y., Hsu, L. 2020; 29 (1): 243–57

  Abstract

  Population attributable fraction is a widely used measure for quantifying the disease burden associated with a modifiable exposure of interest at the population level. It has been extended to a time-varying measure, population attributable hazard function, to provide additional information on when and how the exposure's impact varies over time. However, like the classic population attributable fraction, the population attributable hazard is generally biased if confounders are present. In this article, we provide a natural definition of adjusted population attributable hazard to take into account the effects of confounders, and its alternative that is identifiable from case-control studies under the rare disease assumption. We propose a novel estimator, which combines the odds ratio estimator from logistic regression model, and the conditional density function estimator of the exposure and confounding variables distribution given the failure times of cases or the current times of controls from a kernel smoother. We show that the proposed estimators are consistent and asymptotically normal with variance that can be estimated empirically from the data. Simulation studies demonstrate that the proposed estimators perform well in finite sample sizes. Finally, we illustrate the method by an analysis of a case-control study of colorectal cancer. Supplementary materials for this article are available online.

  View details for DOI 10.1177/0962280219831725

  View details for Web of Science ID 000508982300017

  View details for PubMedID 30799773

  View details for PubMedCentralID PMC7261419

• Phylogenetic Methods Inconsistently Predict the Direction of HIV Transmission Among Heterosexual Pairs in the HPTN 052 Cohort JOURNAL OF INFECTIOUS DISEASES Rose, R., Hall, M., Redd, A. D., Lamers, S., Barbier, A. E., Porcella, S. F., Hudelson, S. E., Piwowar-Manning, E., McCauley, M., Gamble, T., Wilson, E. A., Kumwenda, J., Hosseinipour, M. C., Hakim, J. G., Kumarasamy, N., Chariyalertsak, S., Pilotto, J. H., Grinsztejn, B., Mills, L. A., Makhema, J., Santos, B. R., Chen, Y. Q., Quinn, T. C., Fraser, C., Cohen, M. S., Eshleman, S. H., Laeyendecker, O. 2019; 220 (9): 1406-1413

  Abstract

  We evaluated use of phylogenetic methods to predict the direction of human immunodeficiency virus (HIV) transmission.For 33 pairs of HIV-infected patients (hereafter, "index patients") and their partners who acquired genetically linked HIV infection during the study, samples were collected from partners and index patients close to the time when the partner seroconverted (hereafter, "SC samples"); for 31 pairs, samples collected from the index patient at an earlier time point (hereafter, "early index samples") were also available. Phylogenies were inferred using env next-generation sequences (1 tree per pair/subtype). The direction of transmission (DoT) predicted from each tree was classified as correct or incorrect on the basis of which sequences (those from the index patient or the partner) were closest to the root. DoT was also assessed using maximum parsimony to infer ancestral node states for 100 bootstrap trees.DoT was predicted correctly for both single-pair and subtype-specific trees in 22 pairs (67%) by using SC samples and in 23 pairs (74%) by using early index samples. DoT was predicted incorrectly for 4 pairs (15%) by using SC or early index samples. In the bootstrap analysis, DoT was predicted correctly for 18 pairs (55%) by using SC samples and for 24 pairs (73%) by using early index samples. DoT was predicted incorrectly for 7 pairs (21%) by using SC samples and for 4 pairs (13%) by using early index samples.Phylogenetic methods based solely on the tree topology of HIV env sequences, particularly without consideration of phylogenetic uncertainty, may be insufficient for determining DoT.

  View details for DOI 10.1093/infdis/jiy734

  View details for Web of Science ID 000490992100004

  View details for PubMedID 30590741

  View details for PubMedCentralID PMC6761953

• Estimating Attributable Life Expectancy Under the Proportional Mean Residual Life Model STATISTICS IN BIOSCIENCES Wang, Y., Chen, Y. 2019; 11 (3): 659-676

  Abstract

  In population-based health research, the so-called population attributable fraction is an important quantity that calculates the percentage of excess risk of morbidity and mortality associated with modifiable risk factors for a given population. While the concept of "risk" is usually measured by event probabilities, in practice it may be of a more direct interest to know the excess life expectancy associated with the modifiable risk factors instead, particularly when mortality is of the ultimate concern. In this paper, we thus propose to study a novel quantity, termed "attributable life expectancy," to measure the population attributable fraction of life expectancy. We further develop a model-based approach for the attributable life expectancy under the Oakes-Dasu proportional mean residual life model, and establish its asymptotic properties for inferences. Numerical studies that includes Monte-Carlo simulations and an actual analysis of the mortality associated with smoking cessation in an Asia Cohort Consortium, are conducted to evaluate the performance of our proposed method.

  View details for DOI 10.1007/s12561-019-09258-y

  View details for Web of Science ID 000492545500001

  View details for PubMedID 39575442

  View details for PubMedCentralID PMC11580499

• On a Shape-Invariant Hazard Regression Model with application to an HIV Prevention Study of Mother-to-Child Transmission STATISTICS IN BIOSCIENCES Zheng, C., Chen, Y. 2020; 12 (3): 340–52

  Abstract

  In survival analysis, Cox model is widely used for most clinical trial data. Alternatives include the additive hazard model, the accelerated failure time (AFT) model and a more general transformation model. All these models assume that the effects for all covariates are on the same scale. However, it is possible that for different covariates, the effects are on different scales. In this paper, we propose a shape-invariant hazard regression model that allows us to estimate the multiplicative treatment effect with adjustment of covariates that have non-multiplicative effects. We propose moment-based inference procedures for the regression parameters. We also discuss the risk prediction and the goodness of fit test for our proposed model. Numerical studies show good finite sample performance of our proposed estimator. We applied our method to the HIVNET 012 study, a milestone trial of single-dose nevirapine in prevention of mother-to-child transmission of HIV. From the HIVNET 012 data analysis, single-dose nevirapine treatment is shown to improve 18-month infant survival significantly with appropriate adjustment of the maternal CD4 counts and the virus load.

  View details for DOI 10.1007/s12561-019-09260-4

  View details for Web of Science ID 000491530600002

  View details for PubMedID 33312265

  View details for PubMedCentralID PMC7730855

• Clustering Functional Data with Application to Electronic Medication Adherence Monitoring in HIV Prevention Trials STATISTICS IN BIOSCIENCES Zhu, Y., Di, C., Chen, Y. 2019; 11 (2): 238-261

  Abstract

  Maintaining high medication adherence is essential for achieving desired efficacy in clinical trials, especially prevention trials. However, adherence is traditionally measured by self-reports that are subject to reporting biases and measurement error. Recently, electronic medication dispenser devices have been adopted in several HIV pre-exposure prophylaxis prevention studies. These devices are capable of collecting objective, frequent, and timely drug adherence data. The device opening signals generated by such devices are often represented as regularly or irregularly spaced discrete functional data, which are challenging for statistical analysis. In this paper we focus on clustering the adherence monitoring data from such devices. We first pre-process the raw discrete functional data into smoothed functional data. Parametric mixture models with change-points, as well as several non-parametric and semi-parametric functional clustering approaches are adapted and applied to the smoothed adherence data. Simulation studies were conducted to evaluate finite sample performances, on the choices of tuning parameters in the pre-processing step as well as the relative performance of different clustering algorithms. We applied these methods to the HIV Prevention Trials Network(HPTN) 069 study for identifying subgroups with distinct adherence behavior over the study period.

  View details for DOI 10.1007/s12561-019-09232-8

  View details for Web of Science ID 000478102000003

  View details for PubMedID 31693010

  View details for PubMedCentralID PMC6830730

• HIV testing and the HIV care continuum among sub-Saharan African men who have sex with men and transgender women screened for participation in HPTN 075 PLOS ONE Sandfort, T. G. M., Dominguez, K., Kayange, N., Ogendo, A., Panchia, R., Chen, Y. Q., Chege, W., Cummings, V., Guo, X., Hamilton, E. L., Stirratt, M., Eshleman, S. H. 2019; 14 (5): e0217501

  Abstract

  Throughout the world, men who have sex with men (MSM) are at increased risk for HIV infection compared to heterosexual men. Little is known about awareness of HIV infection and other gaps in the HIV care continuum for MSM, especially in sub-Saharan Africa (SSA). This information is urgently needed to address the HIV epidemic in this population. This study assessed gaps in the HIV care continuum among persons screened for participation in a multi-country prospective study that evaluated the feasibility of recruiting and retaining MSM for HIV prevention studies in SSA (HIV Prevention Trials Network (HPTN) 075, conducted in four cities in Kenya, Malawi, and South Africa). Participants were recruited using site-specific strategies, that included outreach and informal networks. Transgender women (TW) were eligible to participate. During screening, 601 MSM and TW were tested for HIV infection and asked about prior HIV testing, HIV status, engagement in care, and HIV treatment. Viral load testing and retrospective antiretroviral (ARV) drug testing were performed for HIV-infected participants. Most participants (92.2%) had a prior HIV test; 42.1% were last tested >6 months earlier. HIV prevalence was 30.4%. HIV infection was associated with older age and identifying as female or transgender; 43.7% of the HIV-infected participants were newly diagnosed, especially younger persons and persons with a less recent HIV test. Almost a third of previously-diagnosed participants were not linked to care. Most participants (88.7%) in care were on ARV treatment (ART). Only about one-quarter of all HIV-infected participants were virally suppressed. These findings demonstrate substantial prevalence of undiagnosed HIV infection and sub-optimal HIV care engagement among MSM and TW in SSA. Increased HIV testing frequency and better linkage to care represent critical steps in preventing further HIV transmission in this population. Once in care, gaps in the HIV care continuum appear less critical.

  View details for DOI 10.1371/journal.pone.0217501

  View details for Web of Science ID 000469759100060

  View details for PubMedID 31150447

  View details for PubMedCentralID PMC6544251

• Circumcision to prevent HIV and other sexually transmitted infections in men who have sex with men: a systematic review and meta-analysis of global data LANCET GLOBAL HEALTH Yuan, T., Fitzpatrick, T., Ko, N., Cai, Y., Chen, Y., Zhao, J., Li, L., Xu, J., Gu, J., Li, J., Hao, C., Yang, Z., Cai, W., Cheng, C., Luo, Z., Zhang, K., Wu, G., Meng, X., Grulich, A. E., Hao, Y., Zou, H. 2019; 7 (4): E436-E447

  Abstract

  Men who have sex with men (MSM) are disproportionately affected by HIV and other sexually transmitted infections (STIs) worldwide. Previous reviews investigating the role of circumcision in preventing HIV and other STIs among MSM were inconclusive. Many new studies have emerged in the past decade. To inform global prevention strategies for HIV and other STIs among MSM, we reviewed all available evidence on the associations between circumcision and HIV and other STIs among MSM.In this systematic review and meta-analysis, we searched PubMed, Web of Science, BioMed Central, Scopus, ResearchGate, Cochrane Library, Embase, PsycINFO, Google Scholar, and websites of international HIV and STI conferences for studies published before March 8, 2018. Interventional or observational studies containing original quantitative data describing associations between circumcision and incident or prevalent infection of HIV and other STIs among MSM were included. Studies were excluded if MSM could not be distinguished from men who have sex with women only. We calculated pooled odds ratios (ORs) and their 95% CIs using random-effect models. We assessed risk of bias using the Newcastle-Ottawa scale.We identified 62 observational studies including 119 248 MSM. Circumcision was associated with 23% reduced odds of HIV infection among MSM overall (OR 0·77, 95% CI 0·67-0·89; number of estimates [k]=45; heterogeneity I2=77%). Circumcision was protective against HIV infection among MSM in countries of low and middle income (0·58, 0·41-0·83; k=23; I2=77%) but not among MSM in high-income countries (0·99, 0·90-1·09; k=20; I2=40%). Circumcision was associated with reduced odds of herpes simplex virus (HSV) infection among MSM overall (0·84, 0·75-0·95; k=5; I2=0%) and penile human papillomavirus (HPV) infection among HIV-infected MSM (0·71, 0·51-0·99; k=3; I2=0%).We found evidence that circumcision is likely to protect MSM from HIV infection, particularly in countries of low and middle income. Circumcision might also protect MSM from HSV and penile HPV infection. MSM should be included in campaigns promoting circumcision among men in countries of low and middle income. In view of the substantial proportion of MSM in countries of low and middle income who also have sex with women, well designed longitudinal studies differentiating MSM only and bisexual men are needed to clarify the effect of circumcision on male-to-male transmission of HIV and other STIs.National Natural Science Foundation of China, National Science and Technology Major Project of China, Australian National Health and Medical Research Council Early Career Fellowship, Sanming Project of Medicine in Shenzhen, National Institutes of Health, Mega Projects of National Science Research for the 13th Five-Year Plan, Doris Duke Charitable Foundation.

  View details for DOI 10.1016/S2214-109X(18)30567-9

  View details for Web of Science ID 000461370700024

  View details for PubMedID 30879508

  View details for PubMedCentralID PMC7779827

• Pre-exposure prophylaxis initiation and adherence among Black men who have sex with men (MSM) in three US cities: results from the HPTN 073 study JOURNAL OF THE INTERNATIONAL AIDS SOCIETY Wheeler, D. P., Fields, S. D., Beauchamp, G., Chen, Y. Q., Emel, L. M., Hightow-Weidman, L., Hucks-Ortiz, C., Kuo, I., Lucas, J., Magnus, M., Mayer, K. H., Nelson, L. E., Hendrix, C. W., Piwowar-Manning, E., Shoptaw, S., Watkins, P., Watson, C., Wilton, L. 2019; 22 (2): e25223

  Abstract

  Randomized clinical trials have demonstrated the efficacy of antiretroviral pre-exposure prophylaxis (PrEP) in preventing HIV acquisition among men who have sex with men (MSM). However, limited research has examined initiation and adherence to PrEP among Black MSM (BMSM) in the United States (US) who are disproportionately represented among newly HIV infected and late to care individuals. This research reports on the HIV Prevention Trials Network 073 (HPTN 073) study aimed to examine PrEP initiation, utilization and adherence among Black MSM utilizing the theoretically principled, culturally informed and client-centered care coordination (C4) model.The HPTN 073 study enrolled and followed 226 HIV-uninfected Black MSM in three US cities (Los Angeles, CA; Washington DC; and Chapel Hill, NC) from February 2013 through September 2015. Study participants were offered once daily oral emtricitabine/tenofovir (FTC/TDF) PrEP combined with C4 and followed up for 52 weeks. Participants received HIV testing, risk reduction education and clinical monitoring.Of the 226 men enrolled, 178 participants initiated PrEP (79%), and of these 64% demonstrated PrEP utilization at week 26 (mid-point of the study) based on pharmacokinetic testing. Condomless anal sex with an HIV-infected or unknown status casual male partner was statistically significantly associated with a greater likelihood of PrEP initiation (adjusted odds ratio (OR) 4.4, 95% confidence interval (CI) 1.7, 11.7). Greater age (≥25 vs. <25, OR 2.95, 95% CI 1.37 -6.37), perception of having enough money (OR 3.6, 95% CI 1.7 to 7.7) and knowledge of male partner taking PrEP before sex (OR 2.22, 95% CI 1.03 to 4.79) were statistically significantly associated with increased likelihood of PrEP adherence at week 26. Annualized HIV incidence was 2.9 (95% CI 1.2 to 7.9) among those who initiated PrEP, compared to 7.7 (95% CI 2.5 to 24.1) among those who did not initiate PrEP (p = 0.18).Results suggest a high level of PrEP initiation among at-risk Black MSM, a group historically characterized as hard to reach. The data support the importance of addressing contextual factors that affect PrEP initiation and adherence, and of additional research on the ultimate benefit of PrEP in HIV prevention among Black MSM.

  View details for DOI 10.1002/jia2.25223

  View details for Web of Science ID 000460207100002

  View details for PubMedID 30768776

  View details for PubMedCentralID PMC6376611

• Accuracy of Self-Reported HIV Status Among African Men and Transgender Women Who Have Sex with Men Who were Screened for Participation in a Research Study: HPTN 075 AIDS AND BEHAVIOR Fogel, J. M., Sandfort, T., Zhang, Y., Guo, X., Clarke, W., Breaud, A., Cummings, V., Hamilton, E. L., Ogendo, A., Kayange, N., Panchia, R., Dominguez, K., Chen, Y. Q., Eshleman, S. H. 2019; 23 (1): 289-294

  Abstract

  Some HIV-infected individuals in research studies may choose not to disclose knowledge of their HIV status to study staff. We evaluated the accuracy of self-reported HIV status among African men and transgender women who have sex with men and who were screened for a research study. Sixty-seven of 183 HIV-infected participants reported a prior HIV diagnosis. Samples from the remaining 116 participants were tested for antiretroviral (ARV) drugs. Thirty-six of the 116 participants had ARV drugs detected, indicating that they were on antiretroviral treatment; these participants were classified as previously diagnosed based on ARV drug testing. Among participants classified as previously diagnosed, disclosure of a prior HIV diagnosis varied among study sites (p = 0.006) and was more common among those who reported having sex with men only (p = 0.002). ARV drug testing in addition to self-report improves the accuracy for identifying individuals with a prior HIV diagnosis.

  View details for DOI 10.1007/s10461-018-2231-1

  View details for Web of Science ID 000456947200025

  View details for PubMedID 30051192

  View details for PubMedCentralID PMC6344310

• No change in health-related quality of life for at-risk US women and men starting HIV pre-exposure prophylaxis (PrEP): Findings from HPTN 069/ACTG A5305 PLOS ONE Kapadia, S. N., Wu, C., Mayer, K. H., Wilkin, T. J., Amico, K., Landovitz, R. J., Andrade, A., Chen, Y. Q., Chege, W., McCauley, M., Gulick, R. M., Schackman, B. R. 2018; 13 (12): e0206577

  Abstract

  Tenofovir (TDF)-containing PrEP is effective for HIV prevention, but its effect on health-related quality of life (QOL) is unknown. Using data from HPTN 069/ACTG A5305, a randomized study of potential PrEP regimens comparing maraviroc alone, or together with TDF or emtricitabine (FTC), to TDF + FTC (control), we evaluated the impact of these regimens on QOL in at-risk HIV-uninfected U.S. women and men.QOL was measured at baseline (before starting medications) and every 8 weeks through week 48 using the EQ-5D-3L. Responses were converted to a scale from 0.0 (death) to 1.0 (perfect health), using published valuation weights. Mean scores were compared between groups at each time point using nonparametric testing. Multivariable linear regression was used to adjust for potential confounders.We analyzed 186 women (median age 35 years, 65% black, 17% Hispanic) and 405 men (median age 30 years, 28% black, 22% Hispanic), including 9 transgender participants analyzed based on sex-at-birth. Mean baseline QOL was 0.91 for women and 0.95 for men. There were minimal changes in mean QOL over time for any regimen (women: p = 0.29; men: p = 0.14). There were no significant differences between participants who continued the regimen compared to participants who discontinued early (women: p = 0.61; men: p = 0.1). Mean QOL did not differ significantly by regimen at any time point, both unadjusted and after adjustment for age, race/ethnicity, adherence, and use of alcohol, marijuana, opiates, and other substances.QOL in at-risk individuals starting candidate PrEP regimens in a clinical trial is similar to the general population and maintained over time. This finding did not vary among regimens or when adjusted for demographics, adherence, and substance use. Our findings are the first to show that starting a candidate PrEP regimen in at-risk HIV-uninfected U.S. women and men was not associated with significant changes in QOL.Clinicaltrials.gov NCT01505114.

  View details for DOI 10.1371/journal.pone.0206577

  View details for Web of Science ID 000454416400004

  View details for PubMedID 30586364

  View details for PubMedCentralID PMC6306196

• Building effective multilevel HIV prevention partnerships with Black men who have sex with men: experience from HPTN 073, a pre-exposure prophylaxis study in three US cities JOURNAL OF THE INTERNATIONAL AIDS SOCIETY Wheeler, D. P., Lucas, J., Wilton, L., Nelson, L. E., Hucks-Ortiz, C., Watson, C., Hutchinson, C., Mayer, K. H., Kuo, I., Magnus, M., Beauchamp, G., Shoptaw, S., Emel, L., Chen, Y. Q., Hightow-Weidman, L., Fields, S. D. 2018; 21: e25180

  View details for DOI 10.1002/jia2.25180

  View details for Web of Science ID 000447650900007

  View details for PubMedID 30334600

  View details for PubMedCentralID PMC6193312

• Antiretroviral drug use and HIV drug resistance among MSM and transgender women in sub-Saharan Africa AIDS Zhang, Y., Fogel, J. M., Guo, X., Clarke, W., Breaud, A., Cummings, V., Hamilton, E. L., Ogendo, A., Kayange, N., Panchia, R., Dominguez, K., Chen, Y. Q., Sandfort, T., Eshleman, S. H. 2018; 32 (10): 1301-1307

  Abstract

  To analyze antiretroviral drug use and HIV drug resistance among HIV-infected MSM and transgender women who were screened for participation in the HIV Prevention Trials Network 075 study.A qualitative assay was used to detect 20 antiretroviral drugs in five drug classes; this assay is based on liquid chromatography coupled with high-resolution accurate-mass mass spectrometry. HIV viral load testing was performed using the RealTime HIV-1 Viral Load Assay. HIV drug resistance testing was performed using the ViroSeq HIV-1 Genotyping System. Logistic regression was used to evaluate factors associated with study outcomes.Antiretroviral drugs were detected in 63 (34.4%) of 183 participants who had confirmed HIV infection at screening; 11 (17.5%) of the 63 participants were not virally suppressed. Six (54.5%) of the 11 participants had drug-resistant HIV, including four who had multiclass resistance. Seven (63.6%) of the 11 were at risk of acquiring resistance to additional antiretroviral drugs. In multivariate model, antiretroviral drugs were more frequently detected in older participants, those recruited from Kisumu, Kenya, and those who reported ever having been in HIV care or on antiretroviral therapy (ART).Most of HIV-infected persons screened for participation in HIV Prevention Trials Network 075 were not on ART, and many of those who were on ART were not virally suppressed. Many of those participants had drug-resistant HIV. These findings highlight the need for improved HIV care for African MSM and transgender women.

  View details for DOI 10.1097/QAD.0000000000001839

  View details for Web of Science ID 000434301100010

  View details for PubMedID 29794492

  View details for PubMedCentralID PMC6146920

• HIV Drug Resistance in Adults Receiving Early vs. Delayed Antiretroviral Therapy: HPTN 052 JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES Palumbo, P. J., Fogel, J. M., Hudelson, S. E., Wilson, E. A., Hart, S., Hovind, L., Piwowar-Manning, E., Wallis, C., Papathanasopoulos, M. A., Morgado, M. G., Saravanan, S., Tripathy, S., Eron, J. J., Gallant, J. E., McCauley, M., Gamble, T., Hosseinipour, M. C., Kumarasamy, N., Hakim, J. G., Pilotto, J. H., Kumwenda, J., Akelo, V., Godbole, S. V., Santos, B. R., Grinsztejn, B., Panchia, R., Chariyalertsak, S., Makhema, J., Badal-Faesen, S., Chen, Y. Q., Cohen, M. S., Eshleman, S. H. 2018; 77 (5): 484-491

  Abstract

  We evaluated HIV drug resistance in adults who received early vs. delayed antiretroviral therapy (ART) in a multinational trial [HIV Prevention Trials Network (HPTN) 052, enrollment 2005-2010]. In HPTN 052, 1763 index participants were randomized to start ART at a CD4 cell count of 350-550 cells/mm (early ART arm) or <250 cells/mm (delayed ART arm). In May 2011, interim study results showed benefit of early ART, and all participants were offered ART regardless of CD4 cell count; the study ended in 2015.Virologic failure was defined as 2 consecutive viral loads >1000 copies/mL >24 weeks after ART initiation. Drug resistance testing was performed for pretreatment (baseline) and failure samples from participants with virologic failure.HIV genotyping results were obtained for 211/249 participants (128 early ART arm and 83 delayed ART arm) with virologic failure. Drug resistance was detected in 4.7% of participants at baseline; 35.5% had new resistance at failure. In univariate analysis, the frequency of new resistance at failure was lower among participants in the early ART arm (compared with delayed ART arm, P = 0.06; compared with delayed ART arm with ART initiation before May 2011, P = 0.032). In multivariate analysis, higher baseline viral load (P = 0.0008) and ART regimen (efavirenz/lamivudine/zidovudine compared with other regimens, P = 0.024) were independently associated with higher risk of new resistance at failure.In HPTN 052, the frequency of new drug resistance at virologic failure was lower in adults with early ART initiation. The main factor associated with reduced drug resistance with early ART was lower baseline viral load.

  View details for DOI 10.1097/QAI.0000000000001623

  View details for Web of Science ID 000444630800011

  View details for PubMedID 29293156

  View details for PubMedCentralID PMC5844834

• Comparison of Hepatitis B Virus Infection in HIV-Infected and HIV-Uninfected Participants Enrolled in a Multinational Clinical Trial: HPTN 052 JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES Greer, A. E., Ou, S., Wilson, E., Piwowar-Manning, E., Forman, M. S., McCauley, M., Gamble, T., Ruangyuttikarn, C., Hosseinipour, M. C., Kumarasamy, N., Nyirenda, M., Grinsztejn, B., Pilotto, J., Kosashunhanan, N., de Melo, M., Makhema, J., Akelo, V., Panchia, R., Badal-Faesen, S., Chen, Y. Q., Cohen, M. S., Eshleman, S. H., Thio, C. L., Valsamakis, A. 2017; 76 (4): 388-393

  Abstract

  Data comparing hepatitis B virus (HBV) infection in HIV-infected [HIV(+)], and HIV-uninfected [HIV(-)] individuals recruited into the same study are limited. HBV infection status and chronic hepatitis B (cHB) were characterized in a multinational clinical trial: HIV Prevention Trials Network (HPTN 052).HBV infection status at enrollment was compared between HIV(+) (N = 1241) and HIV(-) (N = 1232) from 7 HBV-endemic countries. Hepatitis B e antigen and plasma HBV DNA were determined in cHB. Median CD4, median plasma HIV RNA, and prevalence of transaminase elevation were compared in HIV(+) with and without cHB. Significance was assessed with χ, Fisher exact, and median tests.Among all participants, 33.6% had HBV exposure without cHB (8.9% isolated HBV core antibody, "HBcAb"; 24.7% HBcAb and anti-HB surface antibody positive, "recovered"), 4.3% had cHB, 8.9% were vaccinated, and 53.5% were uninfected. Data were similar among HIV(+) and HIV(-) except for isolated HBcAb, which was more prevalent in HIV(+) than HIV(-) [10.1% vs. 7.7%, P = 0.046]. Median HBV DNA trended higher in HIV(+) than in HIV(-). In HIV(+) with cHB versus those without cHB, transaminase elevations were more prevalent (alanine aminotransferase ≤ grade 2, 12% vs. 5.2%, P = 0.037; aspartate aminotransferase ≤ grade 2, 26% vs. 6.0%, P < 0.001), CD4 trended lower, and HIV RNA was similar.HBV infection status did not differ by HIV infection status. HIV co-infection was associated with isolated HBcAb and a trend of increased HBV DNA. In HIV, cHB was associated with mild transaminase elevations and a trend toward lower CD4.

  View details for DOI 10.1097/QAI.0000000000001511

  View details for Web of Science ID 000423287100011

  View details for PubMedID 28749822

  View details for PubMedCentralID PMC5659928

• Safety and Tolerability of Maraviroc-Containing Regimens to Prevent HIV Infection in Women A Phase 2 Randomized Trial ANNALS OF INTERNAL MEDICINE Gulick, R. M., Wilkin, T. J., Chen, Y. Q., Landovitz, R. J., Amico, K., Young, A. M., Richardson, P., Marzinke, M. A., Hendrix, C. W., Eshleman, S. H., McGowan, I., Cottle, L. M., Andrade, A., Marcus, C., Klingman, K. L., Chege, W., Rinehart, A. R., Rooney, J. F., Andrew, P., Salata, R. A., Siegel, M., Manabe, Y. C., Frank, I., Ho, K., Santana, J., Stekler, J. D., Swaminathan, S., McCauley, M., Hodder, S., Mayer, K. H. 2017; 167 (6): 384-+

  Abstract

  Maraviroc (MVC) is a candidate drug for HIV preexposure prophylaxis (PrEP).To assess the safety and tolerability of MVC-containing PrEP over 48 weeks in U.S. women at risk for HIV infection.Phase 2 randomized, controlled, double-blinded study of 4 antiretroviral regimens used as PrEP. (ClinicalTrials.gov: NCT01505114).12 clinical research sites of the HIV Prevention Trials Network and AIDS Clinical Trials Group.HIV-uninfected women reporting condomless vaginal or anal intercourse with at least 1 man with HIV infection or unknown serostatus within 90 days.MVC only, MVC-emtricitabine (FTC), MVC-tenofovir disoproxil fumarate (TDF), and TDF-FTC (control).At each visit, clinical and laboratory (including HIV) assessments were done. Primary outcomes were grade 3 and 4 adverse events and time to permanent discontinuation of the study regimen. All randomly assigned participants were analyzed according to their original assignment.Among 188 participants, 85% completed follow-up, 11% withdrew early, and 4% were lost to follow-up; 19% discontinued their regimen prematurely. The number discontinuing and the time to discontinuation did not differ among regimens. Grade 3 or 4 adverse events occurred in 5 (MVC), 13 (MVC-FTC), 9 (MVC-TDF), and 8 (TDF-FTC) participants; rates did not differ among regimens. One death (by suicide) occurred in the MVC-TDF group but was judged not to be related to study drugs. Of available plasma samples at week 48 (n = 126), 60% showed detectable drug concentrations. No new HIV infections occurred.Participants were not necessarily at high risk for HIV infection. The regimen comprised 3 pills taken daily. The study was not powered for efficacy.Maraviroc-containing PrEP regimens were safe and well-tolerated compared with TDF-FTC in U.S. women. No new HIV infections occurred, although whether this was due to study drugs or low risk in the population is uncertain. Maraviroc-containing PrEP for women may warrant further study.National Institutes of Health.

  View details for DOI 10.7326/M17-0520

  View details for Web of Science ID 000411009900015

  View details for PubMedID 28828489

  View details for PubMedCentralID PMC5667908

• On Estimation of Time-Dependent Attributable Fraction from Population-Based Case-Control Studies BIOMETRICS Zhao, W., Chen, Y., Hsu, L. 2017; 73 (3): 866-875

  Abstract

  Population attributable fraction (PAF) is widely used to quantify the disease burden associated with a modifiable exposure in a population. It has been extended to a time-varying measure that provides additional information on when and how the exposure's impact varies over time for cohort studies. However, there is no estimation procedure for PAF using data that are collected from population-based case-control studies, which, because of time and cost efficiency, are commonly used for studying genetic and environmental risk factors of disease incidences. In this article, we show that time-varying PAF is identifiable from a case-control study and develop a novel estimator of PAF. Our estimator combines odds ratio estimates from logistic regression models and density estimates of the risk factor distribution conditional on failure times in cases from a kernel smoother. The proposed estimator is shown to be consistent and asymptotically normal with asymptotic variance that can be estimated empirically from the data. Simulation studies demonstrate that the proposed estimator performs well in finite sample sizes. Finally, the method is illustrated by a population-based case-control study of colorectal cancer.

  View details for DOI 10.1111/biom.12648

  View details for Web of Science ID 000411878000018

  View details for PubMedID 28099992

  View details for PubMedCentralID PMC5515699

• Effect of Ganciclovir on IL-6 Levels Among Cytomegalovirus-Seropositive Adults With Critical Illness A Randomized Clinical Trial JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Limaye, A. P., Stapleton, R. D., Peng, L., Gunn, S. R., Kimball, L. E., Hyzy, R., Exline, M. C., Files, D., Morris, P. E., Frankel, S. K., Mikkelsen, M. E., Hite, D., Enfield, K. B., Steingrub, J., O'Brien, J., Parsons, P. E., Cuschieri, J., Wunderink, R. G., Hotchkin, D. L., Chen, Y. Q., Rubenfeld, G. D., Boeckh, M. 2017; 318 (8): 731-740

  Abstract

  The role of cytomegalovirus (CMV) reactivation in mediating adverse clinical outcomes in nonimmunosuppressed adults with critical illness is unknown.To determine whether ganciclovir prophylaxis reduces plasma interleukin 6 (IL-6) levels in CMV-seropositive adults who are critically ill.Double-blind, placebo-controlled, randomized clinical trial (conducted March 10, 2011-April 29, 2016) with a follow-up of 180 days (November 10, 2016) that included 160 CMV-seropositive adults with either sepsis or trauma and respiratory failure at 14 university intensive care units (ICUs) across the United States.Patients were randomized (1:1) to receive either intravenous ganciclovir (5 mg/kg twice daily for 5 days), followed by either intravenous ganciclovir or oral valganciclovir once daily until hospital discharge (n = 84) or to receive matching placebo (n = 76).The primary outcome was change in IL-6 level from day 1 to 14. Secondary outcomes were incidence of CMV reactivation in plasma, mechanical ventilation days, incidence of secondary bacteremia or fungemia, ICU length of stay, mortality, and ventilator-free days (VFDs) at 28 days.Among 160 randomized patients (mean age, 57 years; women, 43%), 156 patients received 1or more dose(s) of study medication, and 132 patients (85%) completed the study. The mean change in plasma IL-6 levels between groups was -0.79 log10 units (-2.06 to 0.48) in the ganciclovir group and -0.79 log10 units (-2.14 to 0.56) in the placebo group (point estimate of difference, 0 [95% CI, -0.3 to 0.3]; P > .99). Among secondary outcomes, CMV reactivation in plasma was significantly lower in the ganciclovir group (12% [10 of 84 patients] vs 39% [28 of 72 patients]); absolute risk difference, -27 (95% CI, -40 to -14), P < .001. The ganciclovir group had more median VFDs in both the intention-to-treat (ITT) group and in the prespecified sepsis subgroup (ITT group: 23 days in ganciclovir group vs 20 days in the placebo group, P = .05; sepsis subgroup, 23 days in the ganciclovir group vs 20 days in the placebo group, P = .03). There were no significant differences between the ganciclovir and placebo groups in duration of mechanical ventilation (5 days for the ganciclovir group vs 6 days for the placebo group, P = .16), incidence of secondary bacteremia or fungemia (15% for the ganciclovir group vs 15% for the placebo group, P = .67), ICU length of stay (8 days for the ganciclovir group vs 8 days for the placebo group, P = .76), or mortality (12% for the ganciclovir group vs 15% for the placebo group, P = .54).Among CMV-seropositive adults with critical illness due to sepsis or trauma, ganciclovir did not reduce IL-6 levels and the current study does not support routine clinical use of ganciclovir as a prophylactic agent in patients with sepsis. Additional research is necessary to determine the clinical efficacy and safety of CMV suppression in this setting.clinicaltrials.gov Identifier: NCT01335932.

  View details for DOI 10.1001/jama.2017.10569

  View details for Web of Science ID 000408095800024

  View details for PubMedID 28829877

  View details for PubMedCentralID PMC5817487

• Impact of Early Antiretroviral Therapy on the Performance of HIV Rapid Tests and HIV Incidence Assays JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES Fogel, J. M., Piwowar-Manning, E., Debevec, B., Walsky, T., Schlusser, K., Laeyendecker, O., Wilson, E. A., McCauley, M., Gamble, T., Tegha, G., Soko, D., Kumwenda, J., Hosseinipour, M. C., Chen, Y. Q., Cohen, M. S., Eshleman, S. H. 2017; 75 (4): 426-430

  Abstract

  Antiretroviral therapy (ART) can downregulate antibody responses to HIV infection. We evaluated the impact of early vs. delayed ART on the performance of HIV diagnostic and incidence assays.Samples were obtained from 207 participants in the HPTN 052 trial, who were stably suppressed on ART for ≥4 years [Malawi sites; pre-ART CD4 cell count 350-550 cells/mm (early ART arm, N = 180) or <250 cells/mm or an AIDS-defining illness (delayed ART arm, N = 27)]. Samples were tested with 2 HIV rapid tests and 2 HIV incidence assays; selected samples were also tested with two fourth-generation immunoassays and a Western blot (WB) assay. A pre-ART sample was analyzed if the follow-up sample had a false-negative or weakly-reactive rapid test result, or had an incidence assay result indicative of recent infection (false-recent result).Ten (4.8%) samples had a nonreactive or weakly-reactive rapid test result (7/180 early ART arm, 3/27 delayed ART arm, P = 0.13); one sample had nonreactive fourth-generation assay results and 3 had indeterminate WBs. Forty (18.9%) samples had a false-recent incidence assay result; 16 (7.8%) had false-recent results with both incidence assays. Baseline samples had stronger rapid test and WB bands, higher fourth-generation assay signal-to-cutoff values, and fewer HIV incidence assay results indicative of recent infection.False-negative/weakly-reactive HIV rapid tests and false-recent HIV incidence assay results were observed in virally-suppressed individuals, regardless of pre-ART CD4 cell count. Downregulation of the antibody response to HIV infection in the setting of ART may impact population-level surveys of HIV prevalence and incidence.

  View details for DOI 10.1097/QAI.0000000000001421

  View details for Web of Science ID 000405554600007

  View details for PubMedID 28471839

  View details for PubMedCentralID PMC5499248

• Estimating a Treatment Effect in Residual Time Quantiles Under the Additive Hazards Model STATISTICS IN BIOSCIENCES Crouch, L., Zheng, C., Chen, Y. 2017; 9 (1): 298-315

  Abstract

  For randomized clinical trials where the endpoint of interest is a time-to-event subject to censoring, estimating the treatment effect has mostly focused on the hazard ratio from the Cox proportional hazards model. Since the model's proportional hazards assumption is not always satisfied, a useful alternative, the so-called additive hazards model, may instead be used to estimate a treatment effect on the difference of hazard functions. Still, the hazards difference may be difficult to grasp intuitively, particularly in a clinical setting of, e.g., patient counseling, or resource planning. In this paper, we study the quantiles of a covariate's conditional survival function in the additive hazards model. Specifically, we estimate the residual time quantiles, i.e., the quantiles of survival times remaining at a given time t, conditional on the survival times greater than t, for a specific covariate in the additive hazards model. We use the estimates to translates the hazards difference into the difference in residual time quantiles, which allows a more direct clinical interpretation. We determine the asymptotic properties, assess the performance via Monte-Carlo simulations, and demonstrate the use of residual time quantiles in two real randomized clinical trials.

  View details for DOI 10.1007/s12561-016-9180-x

  View details for Web of Science ID 000405697000016

  View details for PubMedID 28694879

  View details for PubMedCentralID PMC5501423

• Association of HIV diversity and virologic outcomes in early antiretroviral treatment: HPTN 052 PLOS ONE Palumbo, P. J., Wilson, E. A., Piwowar-Manning, E., McCauley, M., Gamble, T., Kumwenda, N., Makhema, J., Kumarasamy, N., Chariyalertsak, S., Hakim, J. G., Hosseinipour, M. C., Melo, M. G., Godbole, S. V., Pilotto, J. H., Grinsztejn, B., Panchia, R., Chen, Y. Q., Cohen, M. S., Eshleman, S. H., Fogel, J. M. 2017; 12 (5): e0177281

  Abstract

  Higher HIV diversity has been associated with virologic outcomes in children on antiretroviral treatment (ART). We examined the association of HIV diversity with virologic outcomes in adults from the HPTN 052 trial who initiated ART at CD4 cell counts of 350-550 cells/mm3. A high resolution melting (HRM) assay was used to analyze baseline (pre-treatment) HIV diversity in six regions in the HIV genome (two in gag, one in pol, and three in env) from 95 participants who failed ART. We analyzed the association of HIV diversity in each genomic region with baseline (pre-treatment) factors and three clinical outcomes: time to virologic suppression after ART initiation, time to ART failure, and emergence of HIV drug resistance at ART failure. After correcting for multiple comparisons, we did not find any association of baseline HIV diversity with demographic, laboratory, or clinical characteristics. For the 18 analyses performed for clinical outcomes evaluated, there was only one significant association: higher baseline HIV diversity in one of the three HIV env regions was associated with longer time to ART failure (p = 0.008). The HRM diversity assay may be useful in future studies exploring the relationship between HIV diversity and clinical outcomes in individuals with HIV infection.

  View details for DOI 10.1371/journal.pone.0177281

  View details for Web of Science ID 000401313700047

  View details for PubMedID 28481902

  View details for PubMedCentralID PMC5421787

• Phase 2 Study of the Safety and Tolerability of Maraviroc-Containing Regimens to Prevent HIV Infection in Men Who Have Sex With Men (HPTN 069/ACTG A5305) JOURNAL OF INFECTIOUS DISEASES Gulick, R. M., Wilkin, T. J., Chen, Y. Q., Landovitz, R. J., Amico, K., Young, A. M., Richardson, P., Marzinke, M. A., Hendrix, C. W., Eshleman, S. H., McGowan, I., Cottle, L. M., Andrade, A., Marcus, C., Klingman, K. L., Chege, W., Rinehart, A. R., Rooney, J. F., Andrew, P., Salata, R. A., Magnus, M., Farley, J. E., Liu, A., Frank, I., Ho, K., Santana, J., Stekler, J. D., McCauley, M., Mayer, K. H. 2017; 215 (2): 238-246

  Abstract

  Maraviroc (MVC) is a candidate for human immunodeficiency virus (HIV) pre-exposure prophylaxis.Phase 2 48-week safety/tolerability study was conducted, comparing 4 regimens: MVC alone, MVC plus emtricitabine (FTC), MVC plus tenofovir disoproxil fumarate (TDF), and TDF plus FTC. Eligible participants were HIV-uninfected men and transgender women reporting condomless anal intercourse with ≥1 HIV-infected or unknown-serostatus man within 90 days. At each visit, assessments, laboratory testing, and counseling were done. Analyses were intention to treat.Among 406 participants, 84% completed follow-up, 7% stopped early, and 9% were lost to follow-up; 9% discontinued their regimen early. The number discontinuing and the time to discontinuation did not differ among study regimens (P = .60). Rates of grade 3-4 adverse events did not differ among regimens (P = .37). In a randomly selected subset, 77% demonstrated detectable drug concentrations at week 48. Five participants acquired HIV infection (4 MVC alone, 1 MVC + TDF; overall annualized incidence, 1.4% [95% confidence interval, .5%-3.3%], without differences by regimen; P = .32); 2 had undetectable drug concentrations at every visit, 2 had low concentrations at the seroconversion visit, and 1 had variable concentrations.MVC-containing regimens were safe and well tolerated compared with TDF + FTC; this study was not powered for efficacy. Among those acquiring HIV infection, drug concentrations were absent, low, or variable. MVC-containing regimens may warrant further study for pre-exposure prophylaxis.NCT01505114.

  View details for DOI 10.1093/infdis/jiw525

  View details for Web of Science ID 000397204100011

  View details for PubMedID 27811319

  View details for PubMedCentralID PMC5790146

• Virologic outcomes in early antiretroviral treatment: HPTN 052 HIV CLINICAL TRIALS Eshleman, S. H., Wilson, E. A., Zhang, X. C., Ou, S., Piwowar-Manning, E., Eron, J. J., McCauley, M., Gamble, T., Gallant, J. E., Hosseinipour, M. C., Kumarasamy, N., Hakim, J. G., Kalonga, B., Pilotto, J. H., Grinsztejn, B., Godbole, S. V., Chotirosniramit, N., Santos, B., Shava, E., Mills, L. A., Panchia, R., Mwelase, N., Mayer, K. H., Chen, Y. Q., Cohen, M. S., Fogel, J. M. 2017; 18 (3): 100-109

  Abstract

  The HIV Prevention Trials Network (HPTN) 052 trial demonstrated that early antiretroviral therapy (ART) prevented 93% of HIV transmission events in serodiscordant couples. Some linked infections were observed shortly after ART initiation or after virologic failure.To evaluate factors associated with time to viral suppression and virologic failure in participants who initiated ART in HPTN 052.1566 participants who had a viral load (VL) > 400 copies/mL at enrollment were included in the analyses. This included 832 in the early ART arm (CD4 350-550 cells/mm3 at ART initiation) and 734 in the delayed ART arm (204 with a CD4 < 250 cells/mm3 at ART initiation; 530 with any CD4 at ART initiation). Viral suppression was defined as two consecutive VLs ≤ 400 copies/mL after ART initiation; virologic failure was defined as two consecutive VLs > 1000 copies/mL > 24 weeks after ART initiation.Overall, 93% of participants achieved viral suppression by 12 months. The annual incidence of virologic failure was 3.6%. Virologic outcomes were similar in the two study arms. Longer time to viral suppression was associated with younger age, higher VL at ART initiation, and region (Africa vs. Asia). Virologic failure was strongly associated with younger age, lower educational level, and lack of suppression by three months; lower VL and higher CD4 at ART initiation were also associated with virologic failure.Several clinical and demographic factors were identified that were associated with longer time to viral suppression and virologic failure. Recognition of these factors may help optimize ART for HIV treatment and prevention.

  View details for DOI 10.1080/15284336.2017.1311056

  View details for Web of Science ID 000407817100002

  View details for PubMedID 28385131

  View details for PubMedCentralID PMC5633001

• Posterior Estimates of Dynamic Constants in HIV Transmission Modeling COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE Chen, Y., Dale, R., He, H., Le, A. T. 2017; 2017: 1093045

  Abstract

  In this paper, we construct a linear differential system in both continuous time and discrete time to model HIV transmission on the population level. The main question is the determination of parameters based on the posterior information obtained from statistical analysis of the HIV population. We call these parameters dynamic constants in the sense that these constants determine the behavior of the system in various models. There is a long history of using linear or nonlinear dynamic systems to study the HIV population dynamics or other infectious diseases. Nevertheless, the question of determining the dynamic constants in the system has not received much attention. In this paper, we take some initial steps to bridge such a gap. We study the dynamic constants that appear in the linear differential system model in both continuous and discrete time. Our computations are mostly carried out in Matlab.

  View details for DOI 10.1155/2017/1093045

  View details for Web of Science ID 000415856100001

  View details for PubMedID 29250132

  View details for PubMedCentralID PMC5698610

• Treatment as Prevention: Characterization of Partner Infections in the HIV Prevention Trials Network 052 Trial JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES Eshleman, S. H., Hudelson, S. E., Redd, A. D., Swanstrom, R., Ou, S., Zhang, X., Ping, L., Piwowar-Manning, E., Porcella, S. F., Sievers, M. F., Martens, C. A., Bruno, D., Dukhovlinova, E., McCauley, M., Gamble, T., Fogel, J. M., Sabin, D., Quinn, T. C., Gunde, L., Maliwichi, M., Nhando, N., Akelo, V., Moyo, S., Panchia, R., Kumarasamy, N., Chotirosniramit, N., de Melo, M., Pilotto, J., Grinsztejn, B., Mayer, K., Chen, Y. Q., Hughes, J. P., Cohen, M. S. 2017; 74 (1): 112-116

  Abstract

  HIV Prevention Trials Network 052 demonstrated that antiretroviral therapy (ART) prevents HIV transmission in serodiscordant couples. HIV from index-partner pairs was analyzed to determine the genetic linkage status of partner infections. Forty-six infections were classified as linked, indicating that the index was the likely source of the partner's infection. Lack of viral suppression and higher index viral load were associated with linked infection. Eight linked infections were diagnosed after the index started ART: 4 near the time of ART initiation and 4 after ART failure. Linked infections were not observed when the index participant was stably suppressed on ART.

  View details for DOI 10.1097/QAI.0000000000001158

  View details for Web of Science ID 000395994500022

  View details for PubMedID 27532476

  View details for PubMedCentralID PMC5140698

• Preventing HIV-1 Infection in Women Using Oral Preexposure Prophylaxis: A Meta-analysis of Current Evidence JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES Hanscom, B., Janes, H. E., Guarino, P. D., Huang, Y., Brown, E. R., Chen, Y., Hammer, S. M., Gilbert, P. B., Donnell, D. J. 2016; 73 (5): 606-608

  Abstract

  The World Health Organization has issued an early release revision to its antiretroviral guidelines in which PrEP (pre-exposure prophylaxis in the form of daily oral, fixed dose combination tenofovir disoproxil fumarate/emtricitabine) is recommended as a prevention option to all people at substantial risk of acquiring HIV. However, lack of effectiveness in 2 major women-only PrEP trials, VOICE and FEM-PrEP, continues to be a cause for concern about achieving effectiveness for women in Southern Africa. We conducted a series of meta-analyses of oral effectiveness of tenofovir disoproxil fumarate/emtricitabine in women including all 5 randomized placebo-controlled trials that included women. An adherence-based meta-analysis model showed that with high levels of adherence (75%), oral PrEP is estimated to be effective (relative risk = 0.39, 95% confidence interval: 0.25 to 0.60). Provided that these results apply to women in Southern Africa, future prevention trial designs in that region should account for potentially reduced HIV incidence when PrEP is available.

  View details for DOI 10.1097/QAI.0000000000001160

  View details for Web of Science ID 000389045300019

  View details for PubMedID 27846073

  View details for PubMedCentralID PMC5175411

• Antiretroviral Therapy for the Prevention of HIV-1 Transmission NEW ENGLAND JOURNAL OF MEDICINE Cohen, M. S., Chen, Y. Q., McCauley, M., Gamble, T., Hosseinipour, M. C., Kumarasamy, N., Hakim, J. G., Kumwenda, J., Grinsztejn, B., Pilotto, J. S., Godbole, S. V., Chariyalertsak, S., Santos, B. R., Mayer, K. H., Hoffman, I. F., Eshleman, S. H., Piwowar-Manning, E., Cottle, L., Zhang, X. C., Makhema, J., Mills, L. A., Panchia, R., Faesen, S., Eron, J., Gallant, J., Havlir, D., Swindells, S., Elharrar, V., Burns, D., Taha, T. E., Nielsen-Saines, K., Celentano, D. D., Essex, M., Hudelson, S. E., Redd, A. D., Fleming, T. R., HPTN 052 Study Team 2016; 375 (9): 830-839

  Abstract

  An interim analysis of data from the HIV Prevention Trials Network (HPTN) 052 trial showed that antiretroviral therapy (ART) prevented more than 96% of genetically linked infections caused by human immunodeficiency virus type 1 (HIV-1) in serodiscordant couples. ART was then offered to all patients with HIV-1 infection (index participants). The study included more than 5 years of follow-up to assess the durability of such therapy for the prevention of HIV-1 transmission.We randomly assigned 1763 index participants to receive either early or delayed ART. In the early-ART group, 886 participants started therapy at enrollment (CD4+ count, 350 to 550 cells per cubic millimeter). In the delayed-ART group, 877 participants started therapy after two consecutive CD4+ counts fell below 250 cells per cubic millimeter or if an illness indicative of the acquired immunodeficiency syndrome (i.e., an AIDS-defining illness) developed. The primary study end point was the diagnosis of genetically linked HIV-1 infection in the previously HIV-1-negative partner in an intention-to-treat analysis.Index participants were followed for 10,031 person-years; partners were followed for 8509 person-years. Among partners, 78 HIV-1 infections were observed during the trial (annual incidence, 0.9%; 95% confidence interval [CI], 0.7 to 1.1). Viral-linkage status was determined for 72 (92%) of the partner infections. Of these infections, 46 were linked (3 in the early-ART group and 43 in the delayed-ART group; incidence, 0.5%; 95% CI, 0.4 to 0.7) and 26 were unlinked (14 in the early-ART group and 12 in the delayed-ART group; incidence, 0.3%; 95% CI, 0.2 to 0.4). Early ART was associated with a 93% lower risk of linked partner infection than was delayed ART (hazard ratio, 0.07; 95% CI, 0.02 to 0.22). No linked infections were observed when HIV-1 infection was stably suppressed by ART in the index participant.The early initiation of ART led to a sustained decrease in genetically linked HIV-1 infections in sexual partners. (Funded by the National Institute of Allergy and Infectious Diseases; HPTN 052 ClinicalTrials.gov number, NCT00074581 .).

  View details for DOI 10.1056/NEJMoa1600693

  View details for Web of Science ID 000382526000006

  View details for PubMedID 27424812

  View details for PubMedCentralID PMC5049503

• HIV Drug Resistance in Adults Failing Early Antiretroviral Treatment: Results From the HIV Prevention Trials Network 052 Trial JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES Fogel, J. M., Hudelson, S. E., Ou, S., Hart, S., Wallis, C., Morgado, M. G., Saravanan, S., Tripathy, S., Hovind, L., Piwowar-Manning, E., Sabin, D., McCauley, M., Gamble, T., Zhang, X. C., Eron, J. J., Gallant, J. E., Kumwenda, J., Makhema, J., Kumarasamy, N., Chariyalertsak, S., Hakim, J., Badal-Faesen, S., Akelo, V., Hosseinipour, M. C., Santos, B. R., Godbole, S. V., Pilotto, J. H., Grinsztejn, B., Panchia, R., Mayer, K. H., Chen, Y. Q., Cohen, M. S., Eshleman, S. H. 2016; 72 (3): 304-309

  Abstract

  Early initiation of antiretroviral treatment (ART) reduces HIV transmission and has health benefits. HIV drug resistance can limit treatment options and compromise use of ART for HIV prevention. We evaluated drug resistance in 85 participants in the HIV Prevention Trials Network 052 trial who started ART at CD4 counts of 350-550 cells per cubic millimeter and failed ART by May 2011; 8.2% had baseline resistance and 35.3% had resistance at ART failure. High baseline viral load and less education were associated with emergence of resistance at ART failure. Resistance at ART failure was observed in 7 of 8 (87.5%) participants who started ART at lower CD4 cell counts.

  View details for DOI 10.1097/QAI.0000000000000951

  View details for Web of Science ID 000378059800017

  View details for PubMedID 26859828

  View details for PubMedCentralID PMC4911290

• On estimation of covariate-specific residual time quantiles under the proportional hazards model LIFETIME DATA ANALYSIS Crouch, L., May, S., Chen, Y. 2016; 22 (2): 299-319

  Abstract

  Estimation and inference in time-to-event analysis typically focus on hazard functions and their ratios under the Cox proportional hazards model. These hazard functions, while popular in the statistical literature, are not always easily or intuitively communicated in clinical practice, such as in the settings of patient counseling or resource planning. Expressing and comparing quantiles of event times may allow for easier understanding. In this article we focus on residual time, i.e., the remaining time-to-event at an arbitrary time t given that the event has yet to occur by t. In particular, we develop estimation and inference procedures for covariate-specific quantiles of the residual time under the Cox model. Our methods and theory are assessed by simulations, and demonstrated in analysis of two real data sets.

  View details for DOI 10.1007/s10985-015-9332-1

  View details for Web of Science ID 000372952000007

  View details for PubMedID 26058825

  View details for PubMedCentralID PMC4699877